The integrins are α/β heterodimeric cell surface receptors involved in numerous cellular processes from cell adhesion to gene regulation (Hynes, Cell 1992, 69, 11-25; Hemler, Annu. Rev. Immunol. 1990, 8, 365-368). Several integrins have been implicated in disease processes and have generated widespread interest as potential targets for drug discovery (Sharar et al, Springer Semin. Immunopathology 1995, 16, 359-378). In the immune system, integrins are involved in leukocyte trafficking, adhesion and infiltration during inflammatory processes (Nakajima et al, J. Exp. Med. 1994, 179, 1145-1154).
Differential expression of integrins regulates the adhesive properties of cells and different integrins are involved in different inflammatory responses (Butcher et al, Science 1996, 272, 60-66). The α4 integrins, α4β1 (VLA-4) and α4β7 (LPAM), are expressed primarily on monocytes, lymphocytes, eosinophils, basophils, and macrophages but not on neutrophils (Elices et al, Cell 1990, 60, 577-584). The primary ligands for α4 integrins are the endothelial surface proteins mucosal addressin cell adhesion molecule (MAdCAM) and vascular cell adhesion molecule (VCAM) with lower affinity (Makarem et al, J. Biol. Chem. 1994, 269, 4005-4011). The binding of the α4β1 or α4β7 to MAdCAM and/or VCAM expressed on high endothelial venules (HEVs) at sites of inflammation results in firm adhesion of the leukocyte to the endothelium followed by extravasation into the inflamed tissue (Chuluyan et al, Springer Semin. Immunopathology 1995, 16, 391-404). Monoclonal antibodies directed against α4β1, α4β7, MAdCAM or VCAM have been shown to be effective modulators in animal models of chronic inflammatory diseases such as asthma (Simmons et al, Blood 1992, 80, 388-395), rheumatoid arthritis (RA) (Juliano et al, Current Opinion Cell Biology 1993, 5, 812-818), and inflammatory bowel diseases (IBD) (Laberge et al, Am. J. Respir. Crit Care Med. 1995, 151, 822-829 and Barbadillo et al, Springer Semin. Immunopathology 1995, 16). While antibodies have shown efficacy they must be administered parenterally and are inherently cumbersome to produce.
Accordingly, it would be desirable to provide small molecule compounds which inhibit the interaction between α4 integrins and ligands MAdCAM and/or VCAM which would be useful for treatment of chronic inflammatory diseases such as arthritis, asthma, multiple sclerosis, Chrohn's disease, ulcerative colitis, and hepatitis C.